This invention is generally in the field of non-invasive measurement techniques, and relates to a process and apparatus for real-time imaging and sensing (probing) light absorbing agents, such as hemoglobin, in biological tissues.
The following is a list of some prior art patents, documents and articles which are relevant for the better understanding of the background of the invention, as will be described further below:
1. A. Ishimaru, xe2x80x9cWave Propagation and Scattering in Random Mediaxe2x80x9d, Vol. 1, Academic Press (1978)
2. M. Kempe et al., xe2x80x9cAcousto-optic tomography with multiply scattered lightxe2x80x9d, J. Opt. Soc. A., 14, 5, 1151 (1997)
3. WO 89/00278
4. U.S. Pat. No. 5,174,298
5. U.S. Pat. No. 5,286,968
6. U.S. Pat. No. 5,212,667
7. U.S. Pat. No. 5,951,481
8. U.S. Pat. No. 6,041,248
9. WO 95/33987
10. Fay A. Marks et al, xe2x80x9cComprehensive approach to breast cancer detection using light: photon localization by ultrasound modulation and tissue characterization by spectral discriminationxe2x80x9d, SPIE, vol. 1888, pp.500-509.
11. G. D. Mahan et al., xe2x80x9cUltrasonic tagging of light: theoryxe2x80x9d, Proc. Natl. Acad. Sci. USA, 95, 14015, (1998).
12. D. J. Pine et al. xe2x80x9cDynamical correlations of multiply-scattered lightxe2x80x9d, Scattering and Localization of Classical Waves in Random Media, Ping Sheng ed. World Scientific (1990).
13. W. Leutz and G. Maret, xe2x80x9cUltrasonic modulation of multiply scattered lightxe2x80x9d, Physica B, 204, 14-19, (1995).
In recent years, much effort has been devoted to find a technique alternative to Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) for non-invasively probing living biological tissues, such as body organs. MRI and CT involve long procedures and do not always allow real time analysis of measured data. Low-cost, portable and easy-to-use devices have been developed based on near infrared spectroscopy of blood (e.g., pulse oximetry). This technique, however, provides only a global picture of the tissues with a resolution that does not allow functional imaging of the tissue and a reliable diagnosis.
It is well-known that hemoglobin can be found in the body in two different oxygenation statesxe2x80x94oxyhemoglobin and deoxyhemoglobinxe2x80x94which have different light absorption spectra (A. Ishimaru, xe2x80x9cWave Propagation and Scattering in Random Mediaxe2x80x9d, Vol. 1, Academic Press (1978)). In the near infrared range, (690-900 nm), the absorption coefficients of both states of hemoglobin are relatively low. At around 804 mm, both states have exactly the same absorption coefficient, and this point is called xe2x80x9cthe isosbestic pointxe2x80x9d. Therefore, measurement of blood absorption at this wavelength gives a direct indication of the blood volume being tested. At longer wavelengths, the absorption is essentially due to oxyhemoglobin. For example, at or around light wavelengths of 1 micron, the absorption of oxyhemoglobin is more than three times higher than that of the deoxyhemoglobin. Hence, absorption at these wavelengths (0.804 xcexcm and 1 xcexcm) gives a direct indication of the ratio between the two states of hemoglobin.
Hemoglobin oxygenation provides insight on the proper functioning of many body organs such as the brain, breast, liver, heart, etc. Other agents, such as indocyanin green, present absorption in a definite region in the near-infrared range, and can be probed also using infrared light, deeply inside the tissues.
Light propagating inside a scattering medium has two componentsxe2x80x94ballistic and diffuse light. The first component does not experience scattering, while the second corresponds to strongly multi-scattered light (M. Kempe et al., xe2x80x9cAcousto-optic tomography with multiply scattered lightxe2x80x9d, J. Opt. Soc. A., 14, 5, 1151 (1997)). Ballistic light intensity decreases with distance in a scattering medium much more than that of the diffuse light. Therefore, diffuse light can provide information on a scattering medium deep inside it.
It is known in the art to use the diffuse (scattered) light to obtain information on the optical properties of the medium. This is implemented by utilizing an ultrasound wave focused on the particular region under examination inside the medium. Generally, this technique consists of the following: If an ultrasound wave propagates through a region in a scattering medium and an electromagnetic wave (such as a laser light beam) crosses said region and is strongly diffused thereby, the electromagnetic wave frequency is shifted by the frequency of the ultrasound wave (acousto-optic effect) at the location of said region. In other regions, where no interaction between the light and ultrasound waves occurs, the frequency of light is unchanged, and consequently, the detection of the frequency-shifted electromagnetic wave gives direct information on the absorption properties of said region.
WO 89/00278 discloses a technique of ultrasound tagging of light utilizing a continuous ultrasound wave. The manner in which this tagging of light is to be done is, however, physically difficult to implement, since the light detection is obtained using a photo-refractive crystal that requires extremely high intensities.
The ultrasound tagging of light is disclosed also in the following publications: U.S. Pat. Nos. 5,174,298; 5,286,968; 5,212,667; 5,951,481; 6,041,248; WO 95/33987; Fay A. Marks et al, xe2x80x9cComprehensive approach to breast cancer detection using light: photon localization by ultrasound modulation and tissue characterization by spectral discriminationxe2x80x9d, SPIE, vol. 1888, pp. 500-509; and G. D. Mahan et al., xe2x80x9cUltrasonic tagging of light: theoryxe2x80x9d, Proc. Natl. Acad. Sci. USA, 95, 14015, (1998).
U.S. Pat. No. 5,286,968 discloses a technique of multi-channel analog signal detection, aimed at obtaining synchronous detection with a CCD camera. This technique is based on a fast laser modulation.
U.S. Pat. No. 5,212,667 discloses a technique of light imaging in a scattering medium using ultrasound probing and speckle image differencing. According to this technique, coherent laser light impinges onto a scattering medium, disposed between two parallel surfaces, in a direction perpendicular to said surfaces. Light emerging from the medium is a superposition of a multitude of scattered wavelets, each representing a specific scattering part. These wavelets are projected onto the viewing plane of a two-dimensional photodetector array, where they interfere with each other, giving rise to a speckle pattern. Ultrasound pulses propagate into the scattering medium in a direction substantially parallel to said surfaces, and are focused onto the probed region, thereby effecting changes in the position of the scatterers and causing a change in the speckle pattern. This method, however, based as it is on a unidirectional laser beam, has a limited capability of providing information on the scattering medium.
U.S. Pat. No. 5,951,481 discloses a technique for non-invasive measurement of a substance using ultrasound for modulating light that is back-scattered from the region of interest. Here, pulsed ultrasound and a doublet of light pulses are used, and the detected light is not a diffuse light, but a back-scattered, quasi-ballistic light.
U.S. Pat. No. 6,041,248 discloses a technique for frequency encoded ultrasound modulated optical tomography of dense turbid media. This technique utilizes frequency chirped ultrasound and modulated photomultiplier.
There is accordingly a need in the art to facilitate two- or three-dimensional mapping of a region of interest in a scattering medium by providing a novel method and apparatus based on the principle of interaction of diffused light (light that experienced a large number of scattering events in a medium) with ultrasound radiation.
The present invention provides for real-time analysis of data indicative of the detected diffused light affected by said interaction to enable real-time imaging (less than a few seconds per image) and monitoring of a region of interest in the medium (e.g., a blood volume), and/or oxygen saturation, as well as other light absorbing agents within the medium. This technique is based on time and spatial multiplexing of light by a plurality of ultrasound waves at differently located sample volumes (points) in a medium, as well as proper fast signal processing.
The main idea of the present invention consists of providing an acousto-optic interaction between electromagnetic waves (e.g., laser light) and ultrasound pulses in order to localize absorption in a turbid medium (tissues), and affecting the phase of either one of the light or ultrasound signals, or both. By providing a certain phase relationship between ultrasound pulses and/or light signals (the so-called xe2x80x9cphase codingxe2x80x9d), the location of interactions along the axis of propagation of the ultrasound beam (Z-axis) can be provided. In order to locate these interactions in the X-Y plane, the ultrasound beams are directed from a plurality of locations in the X-Y plane. By this, a two or three-dimensional image of a region of interest can be obtained. The ultrasound pulses used in the technique of the present invention are sinusoidal pulses of several (at least one) cycles. An example of such pulses is the Doppler mode used in medical ultrasonography. These Doppler mode pulses are different from doublet pulses that are typically used for echography.
The transmission of ultrasound beams to different locations in the X-Y plane can be implemented by using one or more ultrasound transducers (each operable to periodically transmit ultrasound pulses with a certain phase delay). If a single transducer is used, the X-Y plane is scanned by displacing the transducer. When using a plurality (one- or two-dimensional array) of transducers operating in parallel, each transducer transmitting ultrasound pulses of a frequency slightly different from that of the other transducers, a power spectrum of the temporal trace automatically gives the signal of all frequencies. It is therefore possible to translate the signal in the frequency domain into the transducer""s position in the X-Y plane.
Alternatively, a phase-array of ultrasonic transducers, similar to those typically used in ultrasonic medical imaging, can be used in order to provide the spatial frequency and phase coding. To this end, the electrical signal that is sent to each transducer of the phase-array comprises several frequencies, and phase delays are chosen appropriately for each frequency.
In order to allow identification of the interaction between the electromagnetic and ultrasound radiation components that occur at different locations along the Z-axis, the certain phase relationship between the ultrasound pulses may be obtained by providing different phases of successive ultrasound pulses. Preferably, in order to obtain a sufficient signal-to-noise ratio (SNR) in the detected signal, different phases of the ultrasound pulses are such that each pulse presents a different part of a common sinusoidal signal. Alternatively, ultrasonic pulses with an identical temporal profile may be generated, while the laser intensity is modulated.
There is thus provided according to one aspect of the present invention, a method of detecting the effect of interactions of electromagnetic radiation with ultrasound radiation at different locations within a region of interest in a scattering medium to thereby enable imaging of said medium, the method comprising the steps of:
(i) generating a plurality of sequences of ultrasound pulses, each comprising at least one sinusoidal cycle;
(ii) generating incident electromagnetic radiation of at least one wavelength;
(iii) directing the plurality of sequences of said pulses of ultrasound radiation towards a plurality of locations, respectively, in said region of interest within an X-Y plane perpendicular to axes of propagation of the ultrasound pulses, while illuminating said region of interest with the incident electromagnetic radiation, and controlling phases of either the ultrasound radiation pulses or the electromagnetic radiation components, to thereby produce signals of the electromagnetic radiation, each being a frequency modulated by a frequency of the ultrasound radiation and allowing identification of said interactions that occur at said plurality of locations in the X-Y plane and in a plurality of location along the Z-axis, and;
(iv) detecting the modulated signals of the electromagnetic radiation and generating data indicative thereof, the analysis of said data enabling the imaging of the region of interest.
By appropriately analyzing the detected signals, information on absorbing substances in the region of the medium can be obtained.
According to another aspect of the present invention, there is provided an apparatus for detecting an effect of interactions of electromagnetic radiation with ultrasound radiation pulses at different locations within a region of interest in a scattering medium to thereby enable imaging of said medium, the apparatus comprising:
(a) an ultrasound firing unit comprising a transducer arrangement operable to transmit a plurality of sequences of said pulses of ultrasound radiation to a plurality of locations in said region of interest with an X-Y plane perpendicular to the axes of propagation of the ultrasound pulses; and an electromagnetic radiation source operable to illuminate said region of interest with incident electromagnetic radiation of at least one wavelength, to thereby produce signals of the electromagnetic radiation, each being a frequency modulated by a frequency of the ultrasound radiation and allowing identification of said interactions that occur at said plurality of locations in the X-Y plane and;
(b) a phase control utility associated either with the ultrasound firing unit or with the electromagnetic radiation source, and operable to affect either phases of the ultrasound radiation pulses or phases of the electromagnetic radiation components, to thereby allow identification of said interactions that occur at different locations along the Z-axis;
(c) a detector unit for detecting said modulated signals and generating data indicative thereof; and
(d) a control unit for operating said ultrasound firing unit, said electromagnetic radiation source, and said phase control utility, the control unit comprising a data processing and analyzing utility for analyzing the data generated by the detector to enable said imaging.
The technique of the present invention provides for obtaining a functional image of the region when utilizing the combination of electromagnetic and ultrasound radiation. It should be understood that by means of ultrasound radiation only (i.e., by operating the ultrasound firing unit and a suitable detector), a structural image of the region of interest can be obtained. Hence, by selectively operating the ultrasound firing unit and the electromagnetic radiation source with corresponding detectors, both the functional and structural image can be obtained and registered with each other.